While anti-retrovirals play a critical role in the management of HIV infection, it has become increasingly apparent that by themselves antivirals are incapable of clearing infection. The capacity of HIV-1 to establish a state of latent infection at the level of individual cells provides a mechanism for persistence in the face of highly active anti- retroviral therapy (HAART). Recent lines of evidence support an increased role for immune-based therapies that drive cellular immunity as adjuncts for the treatment of HIV infection. Understanding the ability of such therapies to impact on viral replication, disease progression, protect immune function, allow for immune reconstitution and to impact on viral replication, disease progression, protect immune function, allow for immune reconstitution and to impact viral reservoirs are critical questions in the development of this approach for treatment of HIV infection. This program will focus on the role of therapeutic vaccination for treatment of HIV-1 infection through four interrelated projects. Project 1 (D. Weiner) will test the hypothesis that the cellular immune response can control SIV infection in the context of drug therapy using active (DNA) immunization. Project 2 (R. MacGregor) will clinically evaluate the effects of a prime boost (avipox+DNA+IL-15 plasmid) combination vaccine on the cellular immune response and on viral load in the context of HAART treatment of HIV infection. Project 3 (R. Sekaly) will determine the effect of immune interventions on the CD4 antigen specific immune response using novel Class II tetramer technology. Project 4. (R. Silliciano) will expand the technology he developed for examination of viral reservoirs to macaques and then examine, in the setting of drug therapy, the effects of immune therapy on the size and the decay rate of the viral reservoirs in both humans and macaques. These projects are supported by experienced cores and subcontractors including an experienced Immunology Core (J. Boyer) and Primate subcontract (M. Lewis-SRI) and DNA manufacturing subcontract at Althea inc., (M. Marquet). The program oversight is handled by an experienced Administrative core (D. Weiner) that includes a Steller Scientific Advisor Board.